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Dysfibrinogenemia—Potential Impact of Genotype on Thrombosis or Bleeding
Seminars in Thrombosis and Hemostasis ( IF 3.6 ) Pub Date : 2021-07-14 , DOI: 10.1055/s-0041-1730358
Mustafa Vakur Bor 1 , Søren Feddersen 2 , Inge Søkilde Pedersen 3 , Johannes Jakobsen Sidelmann 1, 4 , Søren Risom Kristensen 5
Affiliation  

The congenital dysfibrinogenemias, most often associated with bleeding disorders, encompass mutations in the amino-terminal end of fibrinogen α-chain consisting of Gly17-Pro18-Arg19-Val20, known as knob A, which is a critical site for fibrin polymerization. Here we review the studies reporting dysfibrinogenemia due to mutations affecting fibrinogen knob A and identified 29 papers. The number of reports on dysfibrinogenemias related to residues Gly17, Pro18, Arg19, and Val20 is 5, 4, 18, and 2, respectively. Dysfibrinogenemias related to residues Gly17, Pro18, and Val20 are exclusively associated with bleeding tendency. However, the clinical picture associated with dysfibrinogenemia related to residue Arg19 varies, with most patients suffering from bleeding tendencies, but also transitory ischemic attacks and retinal thrombosis may occur. The reason for this variation is unclear. To elaborate the genotype–phenotype associations further, we studied a Danish family with knob A-related dysfibrinogenemia caused by the Aα Arg19Gly (p.Arg19Gly) mutation using whole-exome sequencing and fibrin structure analysis. Our family is the first reported carrying the p.Arg19Gly mutation combined with one or more single nucleotide polymorphisms (SNP)s in FGA, FGB, and/or FGG and increased fibrin fiber thickness and fibrin mass-to-length ratio suffering from pulmonary emboli, suggesting that compound genotypes may contribute to the thrombogenic phenotype of these patients. Our review, accordingly, focuses on significance of SNPs, compound genotypes, and fibrin structure measures affecting the genotype–phenotype associations in fibrinogen knob A mutations.



中文翻译:

纤维蛋白原异常——基因型对血栓形成或出血的潜在影响

先天性纤维蛋白原异常血症最常与出血性疾病相关,包括由 Gly17-Pro18-Arg19-Val20 组成的纤维蛋白原 α 链氨基末端的突变,称为旋钮 A,它是纤维蛋白聚合的关键位点。在这里,我们回顾了报告由于影响纤维蛋白原旋钮 A 的突变引起的异常纤维蛋白原血症的研究,并确定了 29 篇论文。与 Gly17、Pro18、Arg19 和 Val20 残基相关的异常纤维蛋白原血症的报告数量分别为 5、4、18 和 2。与 Gly17、Pro18 和 Val20 残基相关的异常纤维蛋白原血症仅与出血倾向有关。然而,与残留 Arg19 相关的异常纤维蛋白原血症相关的临床表现各不相同,大多数患者有出血倾向,但也可能发生短暂性脑缺血发作和视网膜血栓形成。这种变化的原因尚不清楚。为了进一步阐述基因型-表型关联,我们使用全外显子组测序和纤维蛋白结构分析研究了由 Aα Arg19Gly (p.Arg19Gly) 突变引起的旋钮 A 相关异常纤维蛋白原血症的丹麦家庭。我们的家族是第一个报道携带 p.Arg19Gly 突变与一个或多个单核苷酸多态性 (SNP) 的FGAFGB和/或FGG以及增加的纤维蛋白纤维厚度和纤维蛋白质长比患有肺栓塞,表明复合基因型可能有助于这些患者的血栓形成表型。因此,我们的综述侧重于影响纤维蛋白原旋钮 A 突变中基因型-表型关联的 SNP、复合基因型和纤维蛋白结构测量的重要性。

更新日期:2021-07-15
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